Abscisic Acid (“ABA”) is a naturally occurring plant growth regulator that regulates a wide range of plant physiological processes such as seed germination, seedling elongation, abiotic stress response, flowering, and fruit development. The naturally occurring and most biologically active form of ABA is the S enantiomer (S)-ABA. Consequently, a variety of commercial utilities have been identified for (S)-ABA in horticulture and agronomy. (S)-ABA exerts its biological activities by binding to (S)-ABA receptors and activating cellular signal transduction cascades. In addition, (S)-ABA has been demonstrated to have pharmaceutical and nutraceutical utilities (see U.S. Pat. No. 8,536,224).
Synthetic derivatives of ABA may exhibit biological activities either similar to (S)-ABA but with altered (enhanced) potency (ABA agonists) or with a differing spectrum of affinity for the multiple ABA receptors than (S)-ABA itself. Conversely, synthetic derivatives may act biologically in opposition to (S)-ABA (i.e. as ABA antagonists). The synthetic derivatives may also possess improved uptake by plant tissues as well as enhanced metabolic stability. Additionally, synthetic derivatives may have better chemical and environmental stability than (S)-ABA. Thus, synthetic ABA derivatives may possess unique biological activities and have been pursued as an approach to identify novel plant growth regulators.
A variety of synthetic derivatives of ABA have been known in the public domain. Several Japanese research groups have synthesized ABA derivatives with modifications of the side chain and/or with cyclohexenone ring substituents through de novo synthesis (Y. Todoroki, at al., Phytochem. 1995, 38, 561-568; Y. Todoroki, et al., Phytochem. 1995, 40, 633-641; S. Nakano, et al., Biosci. Biotech. Biochem. 1995, 59, 1699-176; Y. Todoroki, et al., Biosci. Biotech. Biochem. 1994, 58, 707-715; Y. Todoroki, et al., Biosci. Biotech. Biochem. 1997, 61, 2043-2045; Y. Todoroki, et al., Tetrahedron, 1996, 52, 8081-8098). Synthesis of (S)-3′-halogen-ABA, (S)-3′-azido-ABA and (S)-alkylthio-ABA from (S)-ABA have also been reported (Y. Todoroki, et al., Tetrahedron, 1995, 51, 6911-6926; S. Arai, et al., Phytochem. 1999, 52, 1185-1193; J. J. Balsevich, et al., Phytochem. 1977, 44, 215-220; Y. Todoroki, et al. Tetrahedron, 2000, 56, 1649-1653; Y. Todoroki, et al., Bioorg. Med. Chem. Lett. 2001, 11, 2381-2384). The work done by S. R. Abrams and coworkers at the Plant Biotechnology Institute at National Research Council of Canada is also noteworthy. Using de novo synthesis approaches, ABA derivatives with modified side-chains or C6′-substitution have been prepared either as racemic mixtures or, in some cases, as pure stereoisomers (see U.S. Pat. No. 5,518,995; D. M. Priest, et al., FEBS Letters, 2005, 579, 4454-4458). A tetralone series of derivatives in which the cyclohexenone ring of (S)-ABA is replaced with a bicyclic tetralone ring has also been described (J. M. Nyangulu, et al., Org. Biomol. Chem. 2006, 4, 1400-1412; J. M. Nyangulu, et al., J. Am. Chem. Soc. 2005, 127, 1662-1664; WO2005/108345).
A few of the examples of (S)-ABA synthetic derivatives prepared in the literature are reported to have biological activity as ABA antagonists. A recent example is the work reported by Takeuchi where a series of (S)-3′-alkylsulfanyl-ABA derivatives were made and tested (Takeuchi, et al., Nature Chem. Biol. 2014, 10, 477-482).
The synthetic ABA derivatives reported in the literature thus far are limited in scope and are typically prepared via multi-step de novo synthesis. The syntheses generally suffer from low overall yields, particularly when the optically pure single enantiomers are desired. Thus, these compounds are generally expensive to synthesize in large quantities or to manufacture on a commercial scale, limiting their commercial application. The (S)-ABA derivatives of the present invention possess the aforementioned biological activities and, more importantly, can be prepared efficiently in single-enantiomer form from (S)-ABA, which until recently was not available in large quantities.
Accordingly, there is a need for enantiomerically pure (S)-ABA derivatives which are agonists and/or antagonists of (S)-ABA with improved or oppositional biological activity, respectively. There is also a need for improved (S)-ABA derivative synthesis methods.